Since many fatal or debilitating inherited defects in blood cell production (e.g. homoglobinopathies) can be accurately diagnosed by chorionic villous biopsy early in gestation, it may be possible to partially reconstitute the defective fetus by transplantating normal hematopoietic stem cells (HSC) obtained from the liver of another similarly preimmune fetus. Transplantation of HSC from fetus to fetus may allow stable chimerism and thus avoid the complications that limit postnatal bone marrow transplantation, i.e. graft rejection and graft vs. host disease (GVHD). Using a naturally occurring pleomorphism at the beta hemoglobin locus in sheep, we have shown that when HSC obtained from early second trimester fetal lamb livers is injected into the peritoneal cavity of similar age allogeneic lamb fetuses, surviving lambs show lasting chimerism without rejection, GVHD, or the need for immunosuppression. Although the sheep model continues to yield information on the hematologic aspects of stem cell replacement, the applicability of this model to human HSC transplantation must be questioned, particularly since the immunologic aspects of engraftment (tolerance induction), may be quite different. We now propose to extend these observations in a rhesus monkey model utilizing simple cytogenetic markers to document engraftment. The rhesus model will allow us to study the effect of gestational age of both the fetal donor and the fetal recipient on the degree of engraftment (the percent of donor cells produced) and its duration after birth. In addition to providing insight into the ontogeny of fetal immunocompetence and the nature of tolerance induction in the fetus, the study of HSC transplantation in the nonhuman primate is critical to clinical application. If the efficacy, feasibility, and safety of in utero HSC transplantation must be clearly delineated in this most rigorous model it may become the first effective therapy of a human genetic disorder.